This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.
Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with xe2x80x9ctraditionalxe2x80x9d antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K+ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythnia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the mininisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 306 871, 308 843 and 655 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal Sci, 9, 429, (1993). Oxabispidine compounds are neither disclosed nor suggested in any of these documents.
Certain oxabispidine compounds are disclosed as chemical curiosities in Chem. Ber., 96, 2872 (1963). That these compounds may be used in the treatment of arrhythmias is neither mentioned nor suggested.
We have surprisingly found that a novel group of oxabispidine-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.
According to the invention there is provided compounds of formula I, 
wherein
R1 represents C1-12 alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het1, xe2x80x94C(O)R5a, xe2x80x94OR5b, xe2x80x94N(R6)R5c, xe2x80x94C(O)XR7, xe2x80x94C(O)N(R8)R5d, and xe2x80x94S(O)2R9), or R1 represents xe2x80x94C(O)XR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2R9;
R5a to R5d independently represent, at each occurrence, H, C1-6 alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, aryl and Het2), aryl or Het3, or R5d, together with R8, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R6 represents H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl), aryl, xe2x80x94C(O)R10a, xe2x80x94C(O)OR10b or xe2x80x94C(O)N(H)R10c;
R10a, R10b and R10c independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl), aryl, or R10a represents H;
R7 represents C1-12 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, aryl, C1-6 alkoxy and Het4);
R8 represents H, C1-12 alkyl, C1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy), xe2x80x94D-aryl, xe2x80x94D-aryloxy, xe2x80x94D-Het5, xe2x80x94Dxe2x80x94N(H)C(O)R11a, xe2x80x94Dxe2x80x94S(O)2R12a, xe2x80x94Dxe2x80x94C(O)R11b, xe2x80x94Dxe2x80x94C(O)OR12b, xe2x80x94Dxe2x80x94C(O)N(R11c)R11d, or R8, together with R5d, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R11a to R11d independently represent H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl), aryl, or R11c and R11d together represent C3-6 alkylene;
R9, R12a and R12b independently represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl) or aryl;
D represents a direct bond or C1-6 alkylene;
X represents O or S;
R2 represents H, halo, C1-6 alkyl, xe2x80x94OR13, xe2x80x94Exe2x80x94N(R14)R15 or, together with R3, representsxe2x95x90O;
R3 represents H, C1-6 alkyl or, together with R2, representsxe2x95x90O;
R13 represents H, C1-6 alkyl, xe2x80x94E-aryl, xe2x80x94E-Het6, xe2x80x94C(O)R16a, xe2x80x94C(O)OR16b or xe2x80x94C(O)N(R17a)R17b;
R14 represents H, C1-6 alkyl, xe2x80x94E-aryl, xe2x80x94E-Het6, xe2x80x94C(O)R16a, OR16b, xe2x80x94S(O)2R16c, xe2x80x94[C(O)]pN(R17a)R17b or xe2x80x94C(NH)NH2;
R15 represents H, C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94C(O)R16d;
R16a to R16d independently represent, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het7), aryl, Het8, or R16a and R16d independently represent H;
R17a and R17b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9), aryl, Het10, or together represent C3-6 alkylene, optionally interrupted by an O atom;
E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene;
p represents 1 or 2;
Het1 to Het10 independently represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from xe2x80x94OH, oxo, halo, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, xe2x80x94N(R18a)R18b, xe2x80x94C(O)R18c, xe2x80x94C(O)OR18d, xe2x80x94C(O)N(R18e)R18f, xe2x80x94N(R18g)C(O)R18h and xe2x80x94N(R18i)S(O)2R18j;
R18a to R18j independently represent C1-6 alkyl, aryl or R18a to R18i independently represent H;
A represents a direct bond, xe2x80x94Jxe2x80x94, xe2x80x94Jxe2x80x94N(R19)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94 (in which latter two groups, N(R19)xe2x80x94 or Oxe2x80x94 is attached to the carbon atom bearing R2 and R3);
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(R20)xe2x80x94, xe2x80x94N(R20)xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94S(O)nxe2x80x94, xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter two groups, Z is attached to the carbon atom bearing R2 and R3), xe2x80x94N(R20)C(O)Oxe2x80x94Zxe2x80x94, (in which latter group, xe2x80x94N(R20) is attached to the carbon atom bearing R2 and R3) or xe2x80x94C(O)N(R20)xe2x80x94 (in which latter group, xe2x80x94C(O) is attached to the carbon atom bearing R2 and R3);
J represents C1-6 alkylene optionally substituted by one or more substituents selected from xe2x80x94OH, halo and amino;
Z represents a direct bond or C1-4 alkylene;
n represents 0, 1 or 2;
R19 and R20 independently represent H or C1-6alkyl;
G represents CH or N;
R4 represents one or more optional substituents selected from xe2x80x94OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by xe2x80x94N(H)C(O)OR21a), C1-6 alkoxy, xe2x80x94N(R22a)R22b, xe2x80x94C(O)R22c, xe2x80x94C(O)OR22d,xe2x80x94C(O)N(R22e)R22f, xe2x80x94N(R22g)C(O)R22h, xe2x80x94N(R22i)C(O)N(R22j)R22k, xe2x80x94N(R22m)S(O)2R21b, xe2x80x94S(O)2R21c, and/or xe2x80x94OS(O)2R21d;
R21a to R21d independently represent C1-6 alkyl;
R22a and R22b independently represent H, C1-6 alkyl or together represent C3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
R22c to R22m independently represent H or C1-6 alkyl; and
R41 to R46 independently represent H or C1-3 alkyl;
wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
provided that
(a) the compound is not:
3,7-dibenzoyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane;
(b) when A represents xe2x80x94Jxe2x80x94N(R19)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94, then:
(i) J does not represent C1 alkylene; and
(ii) B does not represent xe2x80x94N(R20)xe2x80x94, xe2x80x94N(R20)xe2x80x94Zxe2x80x94 (in which latter group N(R20) is attached to the carbon atom bearing R2 and R3), xe2x80x94S(O)nxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R20)C(O)Oxe2x80x94Zxe2x80x94 when R2 and R3 do not together representxe2x95x90O; and
(c) when R2 represents xe2x80x94OR13 or xe2x80x94N(R14)(R15), then:
(i) A does not represent xe2x80x94Jxe2x80x94N(R19)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94; and
(ii) B does not represent xe2x80x94N(R20)xe2x80x94, xe2x80x94N(R20)xe2x80x94Zxe2x80x94 (in which latter group N(R20) is attached to the carbon atom bearing R2 and R3), xe2x80x94S(O)nxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R20)C(O)Oxe2x80x94Zxe2x80x94;
or a pharmaceutically acceptable derivative thereof;
which compounds are referred to hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
Unless otherwise specified, alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkyl and alkoxy groups may also be substituted by one or more halo, and especially fluoro, atoms.
Unless otherwise specified, alkylene groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkylene groups may also be substituted by one or more halo atoms.
The term xe2x80x9carylxe2x80x9d, when used herein, includes C6-10 aryl groups such as phenyl, naphthyl and the like. The term xe2x80x9caryloxyxe2x80x9d, when used herein includes C6-10 aryloxy groups such as phenoxy, naphthoxy and the like. For the avoidance of doubt, aryloxy groups referred to herein are attached to the rest of the molecule via the O-atom of the oxy-group. Unless otherwise specified, aryl and aryloxy groups may be substituted by one or more substituents including xe2x80x94OH, halo, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, xe2x80x94N(R22a)R22b, xe2x80x94C(O)R22c, xe2x80x94C(O)OR22d, xe2x80x94C(O)N(R22e)R22f, xe2x80x94N(R22g)C(O)R22h, xe2x80x94N(R22m)S(O)2R21b, xe2x80x94S(O)2R21c, and/or xe2x80x94OS(O)2R21d (wherein R21b to R21d and R22a to R22m are as hereinbefore defined). When substituted, aryl and aryloxy groups are preferably substituted by between one and three substitutents.
The term xe2x80x9chaloxe2x80x9d, when used herein, includes fluoro, chloro, bromo and iodo.
Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9 and Het10) groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9 and Het10) groups may be fully saturated, wholly aromatic, partly aromatic and/or bicyclic in character. Heterocyclic groups that may be mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzimidazolyl, benzomorpholinyl, benzoxazinonyl, benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, imidazolyl, imidazo[1,2-a]pyridinyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochromanyl, triazolyl and the like. Values of Het1 that may be mentioned include pyridinyl, benzodioxanyl, imidazolyl, imidazo[1,2-a]pyridinyl, piperazinyl, pyrazolyl, pyrrolyl, pyrrolidinyl, tetrahydropyranyl and thiazolyl. Values of Het3 that may be mentioned include benzodioxanyl and benzomorpholinyl. Values of Het4 that may be mentioned include piperazinyl. Substituents on Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9 and Het10) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9 and Het10) groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9 and Het10) groups may also be in the N- or S-oxidised form.
Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Specific salts that may be mentioned include arylsulfonate salts, such as toluenesulfonate and, especially, benzenesulfonate salts. Solvates that may be mentioned include hydrates, such as monohydrates of the compounds of the invention.
Pharmaceutically acceptable derivatives also include, at the oxabispidine or (when G represents N) pyridyl nitrogens, C1-4 alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present:
(a) no Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9 and Het10) group contains an unoxidised S-atom; and/or
(b) n does not represent 0 when B represents xe2x80x94Zxe2x80x94S(O)nxe2x80x94.
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
Abbreviations are listed at the end of this specification.
Compounds of formula I that may be mentioned include those in which, when R2 and R3 together representxe2x95x90O, then A and B do not simultaneously represent direct bonds.
Preferred compounds of the invention include those in which:
R1 represents C1-8 alkyl (which alkyl group is optionally substituted and/or terminated by one or more groups selected from halo, optionally substituted aryl, optionally substituted Het1, xe2x80x94C(O)R5a, xe2x80x94OR5b, xe2x80x94N(R6)R5c, xe2x80x94C(O)N(R8)R5d, and xe2x80x94S(O)2R9), or R1 represents xe2x80x94C(O)OR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2R9;
R5a to R5d independently represent, at each occurrence, H, C1-6 alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from halo, cyano, nitro and aryl), aryl (which latter group is optionally substituted by one or more substituents selected from halo, hydroxy, cyano, nitro, N(R22a)R22b (in which latter group R22a and R22b together represent C3-6 alkylene), C1-4 alkyl and C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms)), Het3, or R5d, together with R8, represents C4-5 alkylene (which alkylene group is optionally interrupted by an O atom);
R6 represents H, C1-6 alkyl, aryl (which latter group is optionally substituted by one or more substituents selected from halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy), xe2x80x94C(O)R10a, xe2x80x94C(O)OR10b or C(O)N(H)R10c;
R10a and R10b independently represent C1-4 alkyl (optionally substituted by one or more substituents selected from halo and aryl) or aryl (which latter group is optionally substituted by or more substituents selected from halo, cyano, nitro, C1-4 alkyl and C1-4 alkoxy);
R10c represents C1-4 alkyl;
R7 represents C1-6 alkyl optionally substituted and/or terminated by one or more substituents selected from halo, aryl, C1-4 alkoxy and Het4;
R8 represents H, C1-6 alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from halo, cyano and nitro), xe2x80x94D-aryl, xe2x80x94D-aryloxy, xe2x80x94D-Het5, xe2x80x94Dxe2x80x94N(H)C(O)R11a, xe2x80x94Dxe2x80x94C(O)R11b, or R8, together with R5d, represents C4-5 alkylene (which alkylene group is optionally interrupted by an O atom);
R11a and R11b independently represent C1-4 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, cyano, nitro and aryl) or aryl;
D represents a direct bond or C1-3 alkylene;
R9 represents C1-6 alkyl (optionally substituted by one or more halo groups) or aryl (which latter group is optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, halo, nitro and cyano);
R2 represents H, halo, C1-3 alkyl, xe2x80x94OR13, xe2x80x94N(H)R14 or, together with R3, representsxe2x95x90O;
R3 represents H, C1-3 alkyl or, together with R2, representsxe2x95x90O;
R13 represents H, C1-4 alkyl, xe2x80x94E-aryl (optionally substituted by one or more substituents selected from cyano, halo, nitro, C1-4 alkyl and C1-4 alkoxy), or xe2x80x94E-Het6;
R14 represents H, C1-6 alkyl, xe2x80x94E-aryl (which aryl group is optionally substituted by one or more substituents selected from cyano, halo, nitro, C1-4 alkyl and C1-4 alkoxy), xe2x80x94C(O)R16a, xe2x80x94C(O)OR16b, xe2x80x94S(O)2R16c, xe2x80x94C(O)N(R17a)R17b or xe2x80x94C(NH)NH2;
R16a to R16c independently represent C1-6 alkyl, or R16a represents H;
R17a and R17b independently represent H or C1-4 alkyl;
E represents a direct bond or C1-2 alkylene;
Het1 to Het6 are optionally substituted by one or more substituents selected from oxo, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy, xe2x80x94N(R18a)R18b, xe2x80x94C(O)R18c or xe2x80x94C(O)OR18d;
R18a to R18d independently represent H, C1-4 alkyl or aryl;
A represents xe2x80x94Jxe2x80x94, xe2x80x94Jxe2x80x94N(R19)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94;
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(R20)xe2x80x94, xe2x80x94N(R20)xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94S(O)nxe2x80x94, xe2x80x94Zxe2x80x94Oxe2x80x94 or xe2x80x94N(R20)C(O)Oxe2x80x94Zxe2x80x94;
J represents C1-4 alkylene;
Z represents a direct bond or C1-3 alkylene;
n represents 0 or 2;
R19 and R20 independently represent H or C1-4 alkyl;
when G represents N, G is in the ortho- or, in particular, the para-position relative to the point of attachment of B;
when G represents N, R4 is absent or represents a single cyano group;
R4 is selected from xe2x80x94OH, cyano, halo, nitro, C1-6 alkyl, C1-6 alkoxy, xe2x80x94C(O)N(R22e)R22f, xe2x80x94N(R22g)C(O)R22h, and/or xe2x80x94N(R22m)S(O)2xe2x80x94C1-4 alkyl;
R22e to R22m independently represent H or C1-4 alkyl;
R41 to R46 independently represent H.
More preferred compounds of the invention include those in which:
R1 represents straight-chain or branched-chain or part cyclic/acyclic C1-6 alkyl optionally interrupted by oxygen and/or optionally substituted and/or terminated by: (i) one or more halo or xe2x80x94OR5b groups; and/or (ii) one group selected from phenyl (which latter group is optionally substituted by one or more substituents selected from halo, cyano and C1-4 alkoxy (which latter group is optionally substituted by one or more halo atoms)), Het1, xe2x80x94C(O)R5a, xe2x80x94N(H)R6, xe2x80x94C(O)N(R8)R5d, and xe2x80x94S(O)2xe2x80x94C1-4 alkyl, or R1 represents xe2x80x94C(O)OR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2xe2x80x94C1-5 alkyl;
Het1 represents a four- (e.g. five-) to ten-membered heterocyclic group containing one or two heteroatoms selected from oxygen, nitrogen and/or sulfur, which group is optionally substituted by one or more substituents selected from C1-2 alkyl and xe2x80x94C(O)xe2x80x94C1-4 alkyl;
R5a, R5b and R5d independently represent H, C1-5 alkyl, phenyl (which latter group is optionally substituted by one or more substituents selected from halo, hydroxy, cyano, pyrrolidinyl, C1-4 alkyl and C1-5 alkoxy (which latter group is optionally substituted by one or more halo atoms)) or Het3;
Het3 represents a five- to ten-membered heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, which group is optionally substituted by one or more substituents selected from oxo, C1-2 alkyl and xe2x80x94C(O)xe2x80x94C1-4 alkyl;
R6 represents H, C1-4 alkyl, phenyl (which latter group is optionally substituted by one or more cyano groups) or xe2x80x94C(O)Oxe2x80x94C1-5 alkyl;
R7 represents C1-5 alkyl optionally substituted or terminated by Het4;
Het4 represents a five- to ten-membered heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, which group is optionally substituted by one or more substituents selected from C1-2 alkyl and xe2x80x94C(O)xe2x80x94C1-4 alkyl;
R8 represents H or C1-4 alkyl;
R2 represents H, xe2x80x94OR13 or xe2x80x94N(H)R14;
R3 represents H;
R13 represents H or phenyl (optionally substituted by one or more substituents selected from cyano and C1-2 alkoxy);
R14 represents H, phenyl (optionally substituted by one or more cyano groups) or xe2x80x94C(O)Oxe2x80x94C1-5 alkyl;
A represents C1-3 alkylene;
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(H)xe2x80x94, xe2x80x94Zxe2x80x94S(O)2xe2x80x94, or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter three groups, Z is attached to the carbon atom bearing R2 and R3);
Z represents a direct bond or C1-2 alkylene;
G represents CH;
R4 represents one or two cyano groups in the ortho- and/or, in particular, the para-position relative to B.
Particularly preferred compounds of the invention include those in which:
R1 represents straight-chain or branched-chain or part cyclic/acyclic C1-6 alkyl optionally interrupted by oxygen and/or optionally substituted and/or terminated by: (i) one or more halo or xe2x80x94OR5b groups; and/or (ii) one group selected from phenyl (which latter group is optionally substituted by one or more substituents selected from halo, cyano and C1-4 alkoxy (which latter group is optionally substituted by one or more halo atoms)), Het1, xe2x80x94C(O)R5a, xe2x80x94N(H)R6, xe2x80x94C(O)N(R8)R5d, and xe2x80x94S(O)2xe2x80x94C1-4 alkyl.
Especially preferred compounds of the invention include those in which:
R1 represents straight- or branched-chain C1-4 alkyl (e.g. C1-3 alkyl) terminated by xe2x80x94C(O)R5a or xe2x80x94N(H)C(O)OR10b;
R5a and R10b independently represent straight- or branched-chain C2-6 alkyl (e.g. C3-5 alkyl, such butyl (e.g. t-butyl));
R2 represents H or OH;
A represents C1-2 alkylene;
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(H)xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter two groups, Z is attached to the carbon atom bearing R2 and R3, and represents C1-2 alkylene);
R4 is a single cyano group in the para-position relative to B.
Preferred compounds of the invention include the compounds of the Examples disclosed hereinafter.
Preferred compounds of the invention also include those in which:
R6 does not represent xe2x80x94C(O)N(H)R10c;
R22a and R22b do not together represent C3-6 alkylene.
Preferred compounds of the invention also include those which are not: tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate; or ethyl 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;
Preparation
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) reaction of a compound of formula II, 
wherein R2, R3, R4, R41 to R46, A, B and G are as hereinbefore defined, with a compound of formula III,
R1xe2x80x94L1xe2x80x83xe2x80x83III
wherein L1 represents a leaving group such as halo, alkanesulfonate, perfluoroalkanesulfonate, arenesulfonate, xe2x80x94OC(O)XR7, imidazole or R23Oxe2x80x94 (wherein R23 represents, for example, C1-10 alkyl or aryl, which groups are optionally substituted by one or more halo or nitro groups) and X, R1 and R7 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. triethylamine, potassium carbonate or a bicarbonate, such as sodium bicarbonate) and an appropriate solvent (e.g. dichloromethane, chloroformn, acetonitrile, N,N-dimethylformamide, THF, toluene, water, a lower alkyl alcohol (e.g. ethanol) or mixtures thereof);
(b) for compounds of formula I in which R1 represents xe2x80x94C(O)XR7 or xe2x80x94C(O)N(R8)R5d, reaction of a compound of formula IV, 
wherein R2, R3, R4, R41 to R46, A, B, G and L1 are as hereinbefore defined, with a compound of formula V,
R24xe2x80x94Hxe2x80x83xe2x80x83V
wherein R24 represents xe2x80x94XR7 or xe2x80x94N(R8)R5d and R5d, R7, R8 and X are as hereinbefore defined, for example under similar conditions to those described hereinbefore (process step (a));
(c) for compounds in which R1 represents xe2x80x94C(O)N(H)R8, reaction of a compound of formula II, as hereinbefore defined, with a compound of formula VI,
R8xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83VI
wherein R8 is as hereinbefore defined, for example at between 0xc2x0 C. and reflux temperature in the presence of an appropriate organic solvent (e.g. dichloromethane), or via solid phase synthesis under conditions known to those skilled in the art;
(d) reaction of a compound of formula VII, 
wherein R1 and R41 to R46 are as hereinbefore defined, with a compound of formula VIII, 
wherein L2 represents a leaving group such as halo, alkanesulfonate (e.g. mesylate), perfluoroalkanesulfonate or arenesulfonate (e.g. 2- or 4-nitrobenzenesulfonate, toluenesulfonate or benzenesulfonate) and R2, R3, R4, A, B and G are as hereinbefore defined, for example at elevated temperature (e.g. between 35xc2x0 C. and reflux temperature) in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile, dichloromethane, chloroform, dimethylsulfoxide, N,N-dimethylformamide, a lower alkyl alcohol (e.g. ethanol), isopropyl acetate or mixtures thereof);
(e) for compounds of formula I in which A represents CH2 and R2 represents xe2x80x94OH or xe2x80x94N(H)R14, reaction of a compound of formula VII, as hereinbefore defined, with a compound of formula IX, 
wherein Y represents O or N(R14) and R3, R4, R14, B and G are as hereinbefore defined, for example at elevated temperature (e.g. 60xc2x0 C. to reflux) in the presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or a mixture of a lower alkyl alcohol and water);
(f) for compounds of formula I in which B represents xe2x80x94Zxe2x80x94Oxe2x80x94, reaction of a compound of formula X, 
wherein R1, R2, R3, R41 to R46, A and Z are as hereinbefore defined, with a compound of formula XI, 
wherein R4 and G are as hereinbefore defined, for example under Mitsunobu-type conditions e.g. at between ambient (e.g. 25xc2x0 C.) and reflux temperature in the presence of a tertiary phosphine (e.g. tributylphosphine or triphenylphosphine), an azodicarboxylate derivative (e.g. diethylazodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperidine) and an appropriate organic solvent (e.g. Dichloromethane or toluene);
(g) for compounds of formula I in which G represents N and B represents xe2x80x94Zxe2x80x94Oxe2x80x94, reaction of a compound of formula X, as hereinbefore defined, with a compound of formula XII, 
wherein R4 and L2 are as hereinbefore defined, for example at between 10xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. sodium hydride) and an appropriate solvent (e.g. N,N-dimethylformamide);
(h) for compounds of formula I in which R2 represents xe2x80x94OR13, in which R13 represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94E-Het6, reaction of a compound of formula I in which R2 represents OH with a compound of formula XIII,
R13aOHxe2x80x83xe2x80x83XIII
wherein R13a represents C1-6 alkyl xe2x80x94E-aryl or xe2x80x94E-Het6 and E and Het6 are as hereinbefore defined, for example under Mitsunobu-type conditions (e.g. as described hereinbefore in process step (f));
(i) for compounds of formula I in which R2 represents xe2x80x94OR13, in which R13 represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94E-Het6, reaction of a compound of formula XIV, 
wherein R1, R3, R4, R41 to R46, A, B, G and L2 are as hereinbefore defined, with a compound of formula XIII, as hereinbefore defined, for example at between ambient (e.g. 25xc2x0 C.) and reflux temperature, under Williamson-type conditions (i.e. in the presence of an appropriate base (e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethylsulfoxide or N,N-dimethylformamide)) (the skilled person will appreciate that certain compounds of formula XIV (e.g. those in which L2 represents halo) may also be regarded as compounds of formula I as hereinbefore defined);
(j) for compounds of formula I in which R2 represents xe2x80x94Exe2x80x94NH2, reduction of a compound of formula XV, 
wherein R1, R3, R4, R41 to R46, A, B, E and G are as hereinbefore defined, for example by hydrogenation at a suitable pressure in the presence of a suitable catalyst (e.g. palladium on carbon) and an appropriate solvent (e.g. a water-ethanol mixture);
(k) for compounds of formula I in which R2 represents xe2x80x94Exe2x80x94N(R14)R15, wherein R14 represents C1-6 alkyl, xe2x80x94E-aryl xe2x80x94E-Het6, xe2x80x94C(O)R16a, xe2x80x94C(O)OR16b, xe2x80x94S(O)2R16c or xe2x80x94C(O)N(R17a)R17b, reaction of a compound of formula I in which R2 represents xe2x80x94Exe2x80x94N(H)R15 with a compound of formula XVI,
R14axe2x80x94L1xe2x80x83xe2x80x83XVI
wherein R14a represents C1-6 alkyl, xe2x80x94E-aryl xe2x80x94E-Het6, xe2x80x94C(O)R16a, xe2x80x94C(O)OR16b, xe2x80x94S(O)2R16c or xe2x80x94C(O)N(R17a)R17b, and R16a, R16b, R16c, R17a, R17b, Het6, E and L1 are as hereinbefore defined, for example under conditions described hereinbefore (process step (a));
(l) for compounds of formula I in which R2 represents xe2x80x94Exe2x80x94N(R15)C(O)N(H)R17a, reaction of a compound of formula I in which R2 represents xe2x80x94Exe2x80x94N(H)R15 with a compound of formula XVII,
R17axe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83XVII
wherein R17a is as hereinbefore defined, for example under conditions described hereinbefore (process step (c));
(m) for compounds of formula I in which R2 represents xe2x80x94Exe2x80x94N(H)[C(O)]2NH2, reaction of a compound of formula I in which R2 represents xe2x80x94Exe2x80x94NH2 with oxalic acid diamide, for example at between xe2x88x9210 and 25xc2x0 C. in the presence of a suitable coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate activating agent (e.g. 1-hydroxybenzotriazole), a suitable base (e.g. triethylamine) and a reaction-inert solvent (e.g. N,N-dimethylformamide);
(n) for compounds of formula I in which R2 represents xe2x80x94Exe2x80x94N(H)C(NH)NH2, reaction of a compound of formula I in which R2 represents xe2x80x94Exe2x80x94NH2 with a compound of formula XVIII,
R23Oxe2x80x94C(xe2x95x90NH)NH2xe2x80x83xe2x80x83XVIII
or an N-protected derivative thereof, wherein R23 is as hereinbefore defined, for example at between room and reflux temperature, optionally in the presence of a suitable solvent (e.g. toluene) and/or an appropriate acidic catalyst (e.g. acetic acid at, for example, 10 mol %);
(o) for compounds of formula I in which R2 represents xe2x80x94OR13, in which R13 represents xe2x80x94C(O)R16a, xe2x80x94C(O)OR16b or xe2x80x94C(O)N(R17a)R17b, reaction of a compound of formula I in which R2 represents xe2x80x94OH with a compound of formula XIX,
R13bxe2x80x94L3xe2x80x83xe2x80x83XIX
wherein R13b represents xe2x80x94C(O)R16a, xe2x80x94C(O)OR16b or xe2x80x94C(O)N(R17a)R17b, L3 represents a leaving group such as halo, p-nitrophenoxy, xe2x80x94OC(O)R16a, xe2x80x94OC(O)OR16b, xe2x80x94OH or imidazole and R16a, R16b, R17a and R17b are as hereinbefore defined, for example at between xe2x88x9210xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. triethylamine, pyridine or potassium carbonate), an appropriate organic solvent (e.g. THF, dichloromethane or acetonitrile) and (where appropriate) a suitable coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide);
(p) for compounds of formula I in which R2 represents H or xe2x80x94OH and R3 represents H, reduction of a compound of formula I in which R2 and R3 together representxe2x95x90O, in the presence of a suitable reducing agent and under appropriate reaction conditions; for example, for formation of compounds of formula I in which R2 represents OH, reduction may be performed under mild reaction conditions in the presence of e.g. sodium borohydride and an appropriate organic solvent (e.g. THF); for formation of compounds of formula I in which R2 represents OH, wherein the compound is enantiomerically enriched (or is a single enantiomer) at the chiral centre to which R2 is attached, reduction may be performed enzymatically (for example under conditions known to those skilled in the art, such as in the presence of horse liver alcohol dehydrogenase and NADPH) or by hydrogenation in the presence of a suitable solution-phase (homogeneous) catalyst under conditions known to those skilled in the art; and for formation of compounds of formula I in which R2 represents H, reduction may be performed either under Wolff-Kisciner conditions known to those skilled in the art or by activating the relevant Cxe2x95x90O group using an appropriate agent (such as tosylhydrazine) in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower (e.g. C1-6) alkyl alcohol);
(q) for compounds of formula I in which R2 represents halo, substitution of a corresponding compound of formula I in which R2 represents xe2x80x94OH, using an appropriate halogenating agent (e.g. for compounds in which R2 represents fluoro, reaction with (diethylamino)sulfur trifluoride);
(r) for compounds of formula I in which R2 and R3 represent H, A represents xe2x80x94Jxe2x80x94 and B represents xe2x80x94N(R20)xe2x80x94Zxe2x80x94 (wherein xe2x80x94N(R20) is attached to the carbon atom bearing R2 and R3), reaction of a compound of formula XX, 
wherein R1, R2, R3, R20, R41 to R46 and J are as hereinbefore defined, with a compound of formula XXI, 
wherein R4, G, Z and L2 are as hereinbefore defined, for example at elevated temperature (e.g. 40xc2x0 C. to reflux) in the presence of a suitable organic solvent (e.g. acetonitrile);
(s) for compounds of formula I in which A represents C2 alkylene and R2 and R3 together representxe2x95x90O, reaction of a compound of formula VII, as hereinbefore defined, with a compound of formula XXII, 
wherein B, G and R4 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. triethylamine, potassium carbonate or tetrabutylammonium hydroxide) and an appropriate organic solvent (e.g. a lower alkl (e.g. C1-6 alcohol);
(t) for compounds of formula I in which R1 represents xe2x80x94C(O)XR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2R9, reaction of a compound of formula XXIII, 
wherein R1a represents xe2x80x94C(O)XR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2R9 and R5d, R7, R8, R9, R41 to R46 and L2 are as hereinbefore defined, with a compound of formula XXIV, 
wherein R2, R3, R4, A, B and G are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. sodium hydrogencarbonate or potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile);
(u) for compounds of formula I which are oxabispidine-nitrogen N-oxide derivatives, oxidation of the corresponding oxabispidine nitrogen of a corresponding compound of formula I, in the presence of a suitable oxidising agent (e.g. mCPBA), for example at 0xc2x0 C. in the presence of a suitable organic solvent (e.g. dichloromethane);
(v) for compounds of formula I which are C1-4 alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a oxabispidine nitrogen, reaction, at the oxabispidine nitrogen, of a corresponding compound of formula I with a compound of formula XXV,
R25xe2x80x94L4xe2x80x83xe2x80x83XXV
wherein R25 represents C1-4 alkyl and L4 is a leaving group such as halo, alkanesulfonate or arenesulfonate, for example at room temperature in the presence of an appropriate organic solvent (e.g. N,N-dimethylformamide), followed by purification (using e.g. HPLC) in the presence of a suitable counter-ion provider (e.g. NH4OAc);
(w) conversion of one R4 substituent to another using techniques well known to those skilled in the art; or
(x) introduction of one or more (further) R4 substituents to the aromatic ring using techniques well known to those skilled in the art (e.g. chlorination).
Compounds of formula II may be prepared by reaction of a compound of formula XXVI, 
wherein R41 to R46 are as hereinbefore defined, with a compound of formula VIII as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (d)), or, in the case of compounds of formula II wherein A represents CH2 and R2 represents xe2x80x94OH or N(H)R14, wherein R14 is as hereinbefore defined, with a compound of formula IX as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (e)).
Compounds of formula IV may be prepared by reaction of a compound of formula II, as hereinbefore defined, with a compound of formula XXVII,
L1xe2x80x94C(O)xe2x80x94L1xe2x80x83xe2x80x83XXVII
wherein L1 is as hereinbefore defined, and in which the two L1 groups may be the same or different, for example at between 0xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. toluene or dichloromethane).
Compounds of formula VII may be prepared by reaction of a compound of formula XXVI, as hereinbefore defined, with a compound of formula III, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (a)), or, in the case of compounds of formula VII wherein R1 represents xe2x80x94C(O)N(H)R8, with a compound of formula VI, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (c)).
Compounds of formula VII wherein R1 represents xe2x80x94C(O)XR7 or xe2x80x94C(O)N(R8)R5d may alternatively be prepared by reaction of a compound of formula XXVI, as hereinbefore defined, with a compound of formula XXVII, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula IV, followed by reaction of the resultant intermediate with a compound of formula V, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (b)).
Compounds of formula VIII may be prepared by standard techniques. For example, compounds of formula VIII in which:
(1) B represents xe2x80x94Zxe2x80x94Oxe2x80x94 may be prepared by coupling a compound of formula XI, as hereinbefore defined, to a compound of formula XXVIII,
L2xe2x80x94Zxe2x80x94C(R2)(R3)xe2x80x94Axe2x80x94L2xe2x80x83xe2x80x83XXVIII
wherein R2, R3, A, Z and L2 are as hereinbefore defined, and the two L2 groups may be the same or different; or
(2) B represents xe2x80x94C(O)N(R20)xe2x80x94 may be prepared by coupling a compound of formula XXIX, 
wherein G, R4 and R20 are as hereinbefore defined, to a compound of formula XXX,
L5xe2x80x94C(O)xe2x80x94C(R2)(R3)xe2x80x94Axe2x80x94L2xe2x80x83xe2x80x83XXX
wherein L5 represents a suitable leaving group (e.g. xe2x80x94OH or halo) and R2, R3, A and L2 are as hereinbefore defined;
in both cases, under conditions which are well known to those skilled in the art.
Compounds of formula VIII in which A represents xe2x80x94(CH2)2xe2x80x94, R2 and R3 both represent H, B represents xe2x80x94CH2xe2x80x94 and G represents CH may be prepared by reaction of a compound of formula XXXA, 
wherein R4 as is hereinbefore defined, but preferably comprises a single ortho- or para-directing substitutable group, such as halo, with succinic anhydride under standard Friedel-Crafts acylation conditions, followed by:
(i) reduction of the resultant intermediate (which may be a two-step process);
(ii) conversion of the terminal hydroxy group to an appropriate L2 group; and, if necessary,
(iii) conversion of one R4 group to another,
all of which steps may be carried out under conditions that are well known no to those skilled in the art.
Compounds of formula VIII in which A represents C1-6 alkylene, B represents a direct bond or C1-4 alkylene, R2 and R3 independently represent H or C1-6 alkyl, provided that when A represents C1 alkylene and B represents a single bond, R2 and R3 both represent H, and G represents CH, may be prepared by coupling a compound of formula XXXB, 
wherein Hal represents fluoro, chloro, bromo or iodo and R4 is as hereinbefore defined, to a compound of formula XXXC, 
wherein R2a and R3a represent H or C1-6 alkyl as appropriate, Aa represents a direct bond or C1-4 alkylene, Bb represents a direct bond or C1-4 alkylene, and Hal, R2 and R3 are as hereinbefore defined, or with a vinyl magnesium halide, for example at between xe2x88x9225xc2x0 C. and room temperature in the presence of a suitable zinc(II) salt (e.g. anhydrous ZnBr2), an appropriate catalyst (e.g. Pd(PPh3)4 or Ni(PPh3)4) and a reaction-inert organic solvent (e.g. THF, toluene or diethyl ether), followed by:
(i) reduction of the resultant intermediate, in the presence of a suitable borane or borane-Lewis base complex (e.g. borane-dimethyl sulfide), an appropriate solvent (e.g. diethyl ether, THF, or a mixture thereof);
(ii) oxidation of the resulting borane adduct with a suitable oxidising agent (e.g. sodium perborate); and
(iii) conversion of the resulting OH group to an L2 group under conditions known to those skilled in the art.
Compounds of formula VIII in which A represents a direct bond or C1-6 alkylene, B represents C2-4 alkylene, R2 and R3 independently represent H or C1-6 alkyl and G represents CH may be prepared by coupling a compound of formula XXXD, 
wherein Ab represents a direct bond or C1-6 alkylene, Bc represents a direct bond or C1-2 alkylene, and R2a and R3a are as hereinbefore defined, or a terminal alkyne equivalent thereof, with a compound of formula XXXB as hereinbefore defined, for example under standard metal-catalysed vinylation conditions, such as Heck conditions (for example in the presence of suitable palladium catalyst system (e.g. Pd(OAc)2 and o-tolylphosphine), for example at between room and reflux temperature in the presence of a suitable solvent (e.g. THF, DMF, dimethyl ether, toluene, water, ethanol or mixtures thereof) and optionally in the presence of an appropriate base (e.g. triethylamine)), or, where the reaction is carried out using a terminal alkyne, under coupling conditions that will be known to those skilled in the art (for example at between room and reflux temperature in the presence of a suitable solvent (e.g. THF, DMF, dimethyl ether, toluene, water, ethanol or mixtures thereof), an appropriate base (e.g. diethylamine) and optionally in the presence of a suitable catalyst (e.g. a copper salt such as copper(I) iodide)), followed by:
(i) hydrogenation of the resultant alkene (or alkyne) intermediate, for example in the presence of a suitable supported palladium catalyst (e.g. Pd on CaCO3 or Pd/C), for example at room temperature in the presence of a suitable solvent (e.g. a lower alkyl alcohol, such as methanol); and
(ii) conversion of the OH group to an L2 group, under conditions known to those skilled in the art.
Compounds of formula VIII in which the group xe2x80x94Axe2x80x94C(R2)(R3)xe2x80x94Bxe2x80x94 represents xe2x80x94(CH2)3-11xe2x80x94 may be prepared by reaction of a corresponding compound of formula VIII in which the group xe2x80x94Axe2x80x94C(R2)(R3)xe2x80x94Bxe2x80x94 represents xe2x80x94(CH2)1-9xe2x80x94 with diethylmalonate using standard malonic ester synthesis, followed by:
(i) reduction of the resultant intermediate; and
(ii) conversion of the terminal hydroxy group to an appropriate L2 group, both of which steps may be carried out under conditions that are well known to those skilled in the art.
Compounds of formula VIII in which A represents C1-6 alkylene, B represents xe2x80x94Zxe2x80x94N(R20)xe2x80x94 (in which latter case, Z is attached to the carbon atom bearing R2 and R3), G represents CH and Z and R20 are as hereinbefore defined, may be prepared by coupling a compound of formula XXXB as hereinbefore defined, to a compound of formula XXXE, 
wherein Ac represents C1-6 alkylene and Z, R20, R2 and R3 are as hereinbefore defined, for example at elevated temperature under conditions well known to those skilled in the art, followed by conversion of the hydroxy group to an L2 group under conditions known to those skilled in the art (for example, where the L2 group is p-toluenesulfonato, the conversion may be carried out by reaction between the intermediate hydroxy compound and p-toluenesulfonyl chloride in the presence of a suitable base (e.g. triethylamine) and an appropriate solvent (e.g. dichloromethane), and optionally in the presence of a suitable catalyst (e.g. DMAP, for example at between 0.1 and 10% (w/w) (e.g. 1% (w/w)) relative to mass of the intermediate hydroxy compound).
Compounds of formula VIII in which A represents a direct bond or C1-6 alkylene, B represents C1-4 alkylene and G represents N may be prepared by coupling a compound of formula XXXF 
wherein R4 is as hereinbefore defined, to a compound of formula XXXG, 
wherein Bc represents a direct bond or C1-3 alkylene and Ac, L2, L5, R2 and R3 are as hereinbefore defined, for example by reacting the compound of formula XXXF with a strong base such as butyl lithium or phenyl lithium (e.g. at xe2x88x9260xc2x0 C., in the presence of a polar solvent, such as THF), followed by addition of the deprotonated intermediate to a compound of formula XXXG (e.g. at xe2x88x9265xc2x0 C.) in the presence of a suitable solvent (such as THF).
Compounds of formula VIII in which A represents C2 alkylene and R2 represents xe2x80x94OR13, in which R13 represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94E-Het6 may alternatively be prepared by reaction of a compound of formula XIII, as hereinbefore defined, with a compound of formula XXXI, 
wherein R3, R4, R25, B and G are as hereinbefore defined, for example at between ambient temperature (e.g. 25xc2x0 C.) and reflux temperature in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functionality to an L2 group (in which L2 is as hereinbefore defined), under conditions that are well known to those skilled in the art.
Compounds of formula IX may be prepared in accordance with techniques which are known to those skilled in the art. For example, compounds of is formula IX in which:
(1) B represents xe2x80x94CH2Oxe2x80x94 and Y represents O may be prepared by reaction of a compound of formula XI, as hereinbefore defined, with a compound of formula XXXII 
wherein R3 and L2 are as hereinbefore defined, for example at elevated temperature (e.g. between 60xc2x0 C. and reflux temperature) in the presence of a suitable base (e.g. potassium carbonate or NaOH) and an appropriate organic solvent (e.g. acetonitrile or toluene/water), or as otherwise described in the prior art;
(2) R3 represents H, B represents a direct bond, C1-4 alkylene, xe2x80x94Zxe2x80x94N(R20)xe2x80x94, xe2x80x94Zxe2x80x94S(O)nxe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which, in each case, the group xe2x80x94Z represents C1-4 alkylene attached to the carbon atom bearing R3) and Y represents O may be prepared by reduction of a compound of formula XXXIIIA or XXXIIIB, 
wherein Ba represents xe2x80x94Zaxe2x80x94N(R20), xe2x80x94Zaxe2x80x94S(O)nxe2x80x94 or xe2x80x94Zaxe2x80x94Oxe2x80x94 (in which groups Za represents a direct bond or C1-3 alkylene attached to the carbon atom bearing R3), and Bb, R4, R20, G and n are as hereinbefore defined, for example at between xe2x88x9215xc2x0 C. and room temperature in the presence of a suitable reducing agent (e.g. NaBH4) and an appropriate organic solvent (e.g. THF), followed by an internal displacement reaction in the resultant intermediate, for example at room temperature in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile);
(3) B represents a direct bond, C1-4 alkylene, xe2x80x94Zxe2x80x94N(R20)xe2x80x94, xe2x80x94Zxe2x80x94S(O)2xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which, in each case, the group Z represents C1-4 alkylene attached to the carbon atom bearing R3) and Y represents O may be prepared by oxidation of a compound of formula XXXIVA or XXXIVB, 
wherein R3, R4, Ba, Bb and G are as hereinbefore defined, in the presence of a suitable oxidising agent (e.g. mCPBA), for example by refluxing in the presence of a suitable organic solvent (e.g. dichioromethane); or
(4) B represents xe2x80x94Zxe2x80x94Oxe2x80x94, in which group Z represents C1-4 alkylene attached to the carbon atom bearing R3, and Y represents xe2x80x94N(R14), wherein R14 represents xe2x80x94C(O)OR16b or xe2x80x94S(O)2R16c, may be prepared by cyclisation of a compound of formula XXXV, 
wherein R14b represents xe2x80x94C(O)OR16b or xe2x80x94S(O)2R16c, Zb represents C1-4 alkylene attached to the carbon atom bearing R3 and R3, R4, R16b, R16c, G and L2 are as hereinbefore defined, for example at between 0xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. sodium hydroxide), an appropriate solvent (e.g. dichloromethane, water, or a mixture thereof) and, if necessary, a phase transfer catalyst (such as tetrabutylammonium hydrogensulfate).
Compounds of formula X may be prepared in a similar fashion to compounds of formula I (see, for example process steps (a) to (e)).
Compounds of formula XIV may be prepared by replacement of the xe2x80x94OH group of a compound of formula I in which R2 represents xe2x80x94OH with an L2 group under conditions that are known to those skilled in the art.
Compounds of formula XV in which E represents a direct bond may be prepared by reaction of a compound of formula I in which R2 represents xe2x80x94OH with a compound of formula XXXVI,
R26S(O)2Clxe2x80x83xe2x80x83XXXVI
wherein R26 represents C1-4 alkyl or aryl (which two groups are optionally substituted by one or more substituents selected from C1-4 alkyl, halo and nitro), for example at between xe2x88x9210 and 25xc2x0 C. in the presence of a suitable solvent (e.g. dichloromethane), followed by reaction with a suitable source of the azide ion (e.g. sodium azide), for example at between ambient and reflux temperature in the presence of an appropriate solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. sodium hydrogencarbonate).
Compounds of formula XV may alternatively be prepared by reaction of a compound of formula VII, as hereinbefore defined, with a compound of formula XXXVII, 
wherein R3, R4, A, B, E, G and L2 are as hereinbefore defined, for example under analogous conditions to those described hereinbefore for the synthesis of compounds of formula I (process step (d)).
Compounds of formula XX may be prepared by removing an optionally substituted benzyloxycarbonyl unit from (i.e. deprotecting) a corresponding compound of formula I in which B represents xe2x80x94N(R20)C(O)OCH2xe2x80x94 and A represents J, wherein R20 and J are as hereinbefore defined, for example under conditions which are known to those skilled in the art.
Compounds of formula XXIII may be prepared by reaction of a compound of formula XXXVIII, 
wherein the wavy bonds indicate optional E-, Z- or mixed E- and Z-geometry about the double bonds, and R1a and R41 to R46 are as hereinbefore defined, with water and a suitable source of the mercury(II) ion (e.g. mercury(II) acetate), for example at between 0 and 30xc2x0 C., optionally in the presence of an appropriate organic solvent (e.g. THF), followed by the conversion of the two resulting mercurialkyl functions to L2 groups, wherein L2 is as hereinbefore defined, under conditions known to those skilled in the art (for example, in the case where L2 represents iodo, reaction with iodine at between room and reflux temperature in the presence of a suitable solvent (e.g. chloroform, water or a mixture thereof)).
Compounds of formula XXIII may alternatively be prepared by reaction of a compound of formula XXXIX, 
wherein R1a and R41 to R46 are as hereinbefore defined, with a reagent that will convert the two xe2x80x94OH functionalities to L2 groups under conditions known to those skilled in the art. For example, this conversion may be achieved, in the case of compounds of formula XXIII wherein L2 represents chloro, bromo or iodo, by reaction of a compound of formula XXXIX with a suitable halogenating agent (for example: triphenylphosphine or bis(diphenylphosphino)ethane combined with the halogen (e.g. bromine or iodine)) in the presence of a suitable base (e.g. imidazole) and a suitable solvent (e.g. dichloromethane, ether and/or acetonitrile), for example as described in Synth. Commun. 1990, 20(10), 1473. Suitable halogenating agents also include: triphenylphosphine combined with carbon tetrachloride, carbon tetrabromide, hexachloroethane or hexachloroacetone; triphenylphosphine dibromide; or triphenylphosphine combined with diethylazodicarboxylate and methyl iodide. In the case of compounds of formula XXIII wherein L2 represents an arenesulfonate or alkanesulfonate (e.g. p-toluenesulfonate, 2- or 4-nitrobenzenesulfonate, methanesulfonate or trifluoromethanesulfonate), the conversion may alternatively be achieved by reaction of a compound of formula XXXIX with an appropriate arenesulfonyl or alkanesulfonyl derivative (e.g. p-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or trifluoromethanesulfonic anhydride), in the presence of a suitable base (e.g. triethylamine, pyridine or N,N-diisopropylethylamine) and an appropriate organic solvent (e.g. dichloromethane or acetonitrile).
Compounds of formula XXVI (or an N-protected derivative thereof) may be prepared from a corresponding compound of formula XL, 
or an N-protected derivative thereof (e.g. where the protecting group is an R1a group, wherein R1a is as hereinbefore defined), wherein R41 to R46 and L2 are as hereinbefore defined, with ammonia (or a protected derivative thereof (e.g. benzylamine)), for example under conditions described hereinbefore for the synthesis of compounds of formula I (process step (t)).
Compounds of formula XXXVII may be prepared in analogous fashion to compounds of formula XV (i.e. from the corresponding alcohol).
Compounds of formula XXXVIII may be prepared by reaction of a compound of formula XLI, 
wherein the wavy bonds indicate optional E-, Z- or mixed E- and Z-geometry about the double bonds, and R41 to R46 are as hereinbefore defined, with a compound of formula III in which R1 represents xe2x80x94C(O)XR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2R9, wherein R5d, R7, R8 and R9 are as hereinbefore defined, for example at between xe2x88x9210 and 25xc2x0 C. in the presence of a suitable base (e.g. NaOH, triethylamine, pyridine or potassium carbonate) and an appropriate solvent (e.g. ether, water, dichloromethane, THF, or mixtures thereof).
Compounds of formula XXXIX may be prepared by reaction of a compound of formula XLII, 
wherein the wavy bonds indicate optional R-, S- or mixed R- and S-stereochemistry at the asymmetric carbon atoms, and R1a and R41 to R46 are as hereinbefore defined, with water, for example at between room and reflux temperature in the presence of a suitable catalyst (e.g. a protic acid such as sulfuric, methanesulfonic or trifluoroacetic acid, an acidic ion-exchange resin such as Amberlyst(copyright) 15 or Nafion(copyright), a Lewis acid such as ZnSO4 or Yb(III) trifluoromethanesulfonate or a base such as sodium hydroxide or tetrabutylammonium hydroxide), an appropriate solvent (e.g. THF, water, 1,4-dioxane or 1-methyl-2-pyrrolidinone, or mixtures thereof (e.g. THF/water)), and optionally (when a basic catalyst is used) in the presence of a suitable phase transfer catalyst (e.g. Triton(copyright) B).
The reaction may be advantageously be performed using compounds of formula XLII having enantiomeric (or diastereomeric) enrichment at the chiral centres identified above. The use of such enantiomerically- (or diastereomerically-) enriched compounds of formula XLII in the formation of compounds of formula XXXIX may have the advantage that a greater proportion of the product diol is obtained as the cis-isomer (i.e. the conformation of compounds of formula XXXIX depicted above). Those skilled in the art will appreciate that such an increased proportion of cis-isomer may be retained in the conversion of compounds of formula XXXIX to compounds of formula XXIII, and thus may eventually lead to a higher yield of compounds of formula I (via process step (t)).
The reaction may also be advantageously performed using compounds of formula XLII wherein R1a represents xe2x80x94S(O)2R9 (e.g. wherein R9 represents optionally substituted phenyl, such as 2- or 4-fluorophenyl, 2- or 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or 4-nitrophenyl, 2,4,6-trimethylphenyl). The use of such ring-substituted benzenesulfonyl derivatives may have the advantage that purification of the resulting compound of formula XXXIX may be made more straightforward (e.g. requiring only a simple recrystallisation step) and/or that, in a compound of formula I (synthesised via compounds of formulae XXXIX and XXIII), removal of the xe2x80x94S(O)2R9 group (allowing its replacement with another R1 group) may be made more straightforward (e.g. enabling the use of milder reaction conditions).
Compounds of formula XL may be prepared in an analogous fashion to compounds of formula XXIII, as hereinbefore defined (i.e. from e.g. the corresponding diallylamine).
Compounds of formula XLII in which the substituent R42 has the same identity as R41, R44 has the same identity as R43 and R46 has the same identity as R45 may be prepared by reaction of two or more equivalents of a compound of formula XLIII, 
wherein the wavy bond indicates optional R-, S- or mixed R- and S-stereochemistry at the asymmetric carbon atom, and R41, R43, R45 and L2 are as hereinbefore defined, with one equivalent of a compound of formula XLIV,
R1aNH2xe2x80x83xe2x80x83XLIV
wherein R1a is as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. an alkali metal carbonate such as cesium carbonate, sodium hydroxide, sodium hydride or lithium diisopropylamide), an appropriate solvent (e.g. acetonitrile, N,N-dimethylformamide, THF, toluene, water or mixtures thereof), and optionally in the presence of a phase transfer catalyst (e.g. tricaprylyl-methylammonium chloride). Preferred bases include sodium hydroxide and preferred solvents include water. The reaction is advantageously performed with compounds of formula XLIV wherein R1a represents xe2x80x94S(O)2R9 (e.g. wherein R9 represents optionally substituted phenyl, such as 2- or 4-fluorophenyl, 2- or 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or 4-nitrophenyl, 2,4,6-trimethylphenyl). The use of such ring-substituted benzenesulfonyl derivatives may have the advantage that purification of the resulting compound of formula XLII may be made more straightforward (e.g. requiring only a simple recrystallisation step).
Compounds of formulae XLIII and XLIV may also be reacted together in this way in the presence of water in order to give a direct, xe2x80x9cone-potxe2x80x9d process providing a compound of formula XXXIX. Such xe2x80x9cone-potxe2x80x9d reactions may be carried out, for example, by using a biphasic reaction mixture comprising a solution of XLIII and XLIV in an organic solvent (e.g. toluene), and an aqueous solution of a base (e.g. sodium hydroxide). Alternatively, the aqueous solution of base may, after the formation of the intermediate compound of formula XLII is complete, be exchanged for an aqueous solution of an acid (e.g. either a protic or a Lewis acid). Any of the reaction steps in such biphasic mixtures may be carried out in the presence of a suitable phase transfer catalyst.
Compounds of formula XLII having enantiomeric (or diastereomeric) enrichment at the chiral centres identified above may be prepared by reaction of a compound of formula XLIV, as hereinbefore defined, with a compound of formula XLIII, as hereinbefore defined, having enantiomeric enrichment at the carbon atom to which R43 is attached. Those skilled in the art will realise that this will lead to more of the isomer(s) required for further elaboration to compounds of formula I.
Compounds of formula XLII may alternatively be prepared by reaction of a compound of formula XXXVIII, as hereinbefore defined, with a suitable oxidising agent. Suitable conditions for this oxidation include, for example, reaction at between xe2x88x9225xc2x0 C. and reflux temperature with a suitable peroxide or peracid (e.g. hydrogen peroxide, tert-butyl hydroperoxide or mCPBA), optionally in the presence of an appropriate solvent (e.g. dichloromethane, t-butanol, nitromethane, toluene, water, or mixtures thereof), a suitable catalyst (for example a protic acid, a Lewis acid, or a metal complex capable of forming a peroxide adduct, such as methyltrioxorhenium(VII) or a combination of sodium tungstate and (aminomethyl)phosphonic acid), and/or further appropriate additives (for example: in the case of oxidations carried out with methyltrioxorhenium(VII) and hydrogen peroxide, a basic additive such as pyridine or pyrazole; and in the case of oxidations with sodium tungstate and hydrogen peroxide, a phase transfer catalyst such as methyltri-n-octylammonium hydrogensulfate). Particular embodiments of this oxidation are described in patent applications EP A1 0 380 085 and WO 98/33786 A1, the disclosures in which documents are hereby incorporated by reference. When the oxidation is carried out in the presence of both a catalyst and water, one embodiment of the reaction involves a xe2x80x9cone-potxe2x80x9d conversion of the compound of formula XXXVIII to a compound of formula XXXIX, as hereinbefore defined. This reaction proceeds via the catalysed hydrolysis of the intermediate compound of formula XLII.
Compounds of formula XLII in which the two epoxide chains are not identical (e.g. where R41 and R42 are not identical) may be prepared by reaction of a compound of formula XLIII, as hereinbefore defined, with a compound of formula XLV, 
wherein the wavy bond indicates optional R-, S- or mixed R- and S-stereochemistry at the asymmetric carbon atom, and R1a, R42, R44, and R46 are as hereinbefore defined, for example under conditions described hereinbefore for the synthesis of symmetrical compounds of formula XLII.
Compounds of formula XLV may be prepared by reaction of one or more equivalents of a compound of formula XLIV, as hereinbefore defined, with one equivalent of a compound of formula XLIII, for example under conditions as described hereinbefore for reaction between these two compounds.
Compounds of formula XLV may alternatively be prepared by oxidation of a corresponding compound of formula XLVI, 
wherein the wavy bond indicates optional E-, Z- or mixed E- and Z-geometry about the double bond, and R1a, R42, R44 and R46 are as hereinbefore defined, for example under conditions as hereinbefore described for the synthesis of compounds of formula XLII.
Compounds of formula I may also be prepared, advantageously, by dehydrative cyclisation of compound of formula XLVII, 
wherein A, B, G, R1, R2, R3, R4 and R41 to R46 are as hereinbefore defined, for example in the presence of a suitable dehydrating agent (such as: a strong acid (e.g. sulfuric acid (e.g. concentrated sulfuric acid), methanesulfonic acid (e.g. anhydrous methanesulfonic acid) and the like; an acid anhydride such as acetic anhydride or trifluoromethane-sulfonic anhydride; P2O5 in methanesulfonic acid; a phosphorous-based halogenating agent such as P(O)Cl3, PCl3 or PCl5; and thionyl chloride).
This cyclisation process may be carried out in the presence of a suitable organic solvent system, which solvent system should not significantly react chemically with, or significantly give rise to stereochemical changes in, the reactants or product once formed, or significantly give rise to other side reactions. Preferred solvent systems include aromatic hydrocarbons (e.g. toluene or xylene).
This cyclisation process may be carried out at elevated temperature (e.g. up to the reflux temperature of the relevant solvent system, or higher if a pressurised system is employed). Clearly, appropriate reaction times and reaction temperatures depend upon the solvent system that is employed, as well as the reactants that are used and the compound that is to be formed, but these may be determined routinely by the skilled person.
Compounds of formula XLVII may advantageously be prepared by reaction of a compound of formula XLVIII, 
wherein the wavy bonds indicate optional R-, S- or mixed R- and S-stereochemistry at the asymmetric carbon atoms, and R1 and R41 to R46 are as hereinbefore defined, with a compound of formula XXIV as hereinbefore defined. This reaction may be carried out at between room temperature and the reflux temperature of any solvent that is employed. Suitable solvent systems that may be employed include organic solvent systems, which system should not significantly react chemically with, or significantly give rise to stereochemical changes in, the reactants or product once formed, or significantly give rise to other side reactions. Preferred solvent systems include lower alkyl alcohols (particularly primary alcohols (e.g. ethanol)) optionally in the presence of water, IMS, aromatic hydrocarbons (e.g. toluene) or mixtures thereof.
Compounds of formula XXIV may be prepared as described herein. Compounds of formula XLVIII may be prepared according to or by analogy with the procedures described herein in relation to the preparation of compounds of formula XLII.
The formation of compounds of formula XLVII may be also be performed using compounds of formula XLVIII having enantiomeric (or diastereomeric) enrichment at the chiral centres identified hereinbefore. The use of such enantiomerically- (or diastereomerically-) enriched compounds of formula XLVIII in the formation of compounds of formula XLVII may have the advantage that a greater proportion of the product diol is obtained in a form (e.g. the trans-form) which facilitates the subsequent cyclisation, leading to a higher yield of compounds of formula I.
The formation of compounds of formula XLVII is preferably carried out using compounds of formula XLVIII in which R1 represents R1a, wherein R1a is as hereinbefore defined. The formation of compounds of formula XLVII is more preferably carried out using compounds of formula XLVIII in which R1 represents xe2x80x94S(O)2R9 (e.g. wherein R9 represents optionally substituted phenyl, such as 2- or 4-fluorophenyl, 2- or 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or 4-nitrophenyl, 2,4,6-trimethylphenyl and, especially, unsubstituted phenyl).
Preferred compounds of formula XXIV include those in which:
G represents CH;
A represents a direct bond;
B represents a direct bond;
R2 represents H or C1-6 alkyl;
R3 represents H or C1-6 alkyl;
R4 is absent or represents one to three halo, methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro.
We have found, surprisingly, that, when compounds of formula I are formed using this process (i.e. via compounds of formula XLVII), the employment of derivatives of formula XLVIII in which R1 represents R1a (e.g. wherein R1a represents optionally-substituted benzenesulfonyl, such as described above), and benzylamine-type derivatives of formula XXIV (such as those described above), may have the advantage that, in the resultant compound of formula I, the presence of the R1a (e.g. xe2x80x94S(O)2R9 group and/or the benzylarnine-type group allows for direct and facile replacement of that/those group(s) with other R1 groups, and/or 
fragments, as appropriate, for example by employing reactions that are akin to xe2x80x9cdeprotectionxe2x80x9d reactions (see below), and subsequently performing coupling reactions (see, for example process steps (a), (c), (d) and (e)). We have found, if that benzenesulfonyl derivatives of formula XLVIII, and benzylamine-type derivatives of formula XXIV are employed, subsequent replacement steps may be made more straightforward (e.g. enabling the use of milder reaction conditions).
In this respect, certain compounds of the invention may further be employed as intermediates, useful in the manufacture of other compounds of the invention. Such compounds include, but are not limited to compounds of formula I in which:
R1 represents xe2x80x94S(O)2R9, wherein R9 represents optionally substituted phenyl, such as 2- or 4-fluorophenyl, 2- or 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- or 4-nitrophenyl, 2,4,6-trimethylphenyl and, especially, unsubstituted phenyl;
R41 to R46 all represent H;
G represents CH;
A represents a direct bond;
B represents a direct bond;
R2 represents H or C1-6 alkyl;
R3 represents H or C1-6 alkyl;
R4 is absent or represents one to three halo, methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro.
Compounds of formula I that may, in particular, be employed as intermediates include, but are not limited to those in which:
R2 and R3 both represent H;
R4 is absent; and/or
R9 represents unsubstituted phenyl.
Further, compounds of formula I in which:
R41 to R46 all represent H;
R1 represents straight- or branched-chain C1-4 alkyl (e.g. C1-3 alkyl, such as methyl) terminated by C(O)R5a or xe2x80x94N(H)C(O)OR10b;
R5a and R10b independently represent straight- or branched-chain C2-6 alkyl (e.g. C3-5 alkyl, such butyl (e.g. t-butyl));
R2 represents H or OH;
R3 represents H;
A represents C1 alkylene or linear C2 alkylene;
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(H)xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter two groups, Z is attached to the carbon atom bearing R2 and R3, and represents C1 alkylene or linear C2 alkylene);
G represents CH; and
R4 is a single cyano group in the para-position relative to B, may be prepared by a process which comprises the steps of:
(i) removal of the xe2x80x94SO2R9 group from a compound of formula I in which R1 represents xe2x80x94S(O)2R9, wherein R9 represents optionally substituted phenyl, R41 to R46 all represent H, G represents CH, A and B both represent direct bonds, R2 and R3 independently represent H or C1-6 alkyl and R4 is absent or represents one to three halo, methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro, to provide a compound of formula II as hereinbefore defined, in which R41 to R46 all represent H, G represents CH, A and B both represent direct bonds, R2 and R3 independently represent H or C1-6 alkyl and R4 is absent or represents one to three halo, methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro, for example using standard deprotection conditions (e.g. in the presence of a standard deprotecting agent (such a hydrohalic acid (e.g. HBr, especially concentrated aqueous HBr) or a reducing agent such as LiAlH4), at or above room temperature (e.g. at reflux) with or without the presence of a solvent;
(ii) reaction of the resultant compound of formula II with a compound of formula III, as hereinbefore defined, in which R1 represents straight- or branched-chain C1-4 alkyl (e.g. C1-3 alkyl, such as methyl) terminated by C(O)R5a or xe2x80x94N(H)C(O)OR10b, in which R5a and R10b independently represent straight- or branched-chain C2-6 alkyl (e.g. C3-5 alkyl, such butyl (e.g. t-butyl)), to form a compound of formula I in which R1 represents straight- or branched-chain C1-4 alkyl (e.g. C1-3 alkyl, such as methyl) terminated by C(O)R5a or xe2x80x94N(H)C(O)OR10b, R5a and R10b independently represent straight- or branched-chain C2-6 alkyl (e.g. C3-5 alkyl, such butyl (e.g. t-butyl)), R41 to R46 all represent H, G represents CH, A and B both represent a direct bond, R2 and R3 independently represent H or C1-6 alkyl and R4 is absent or represents one to three halo, methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro, for example under conditions described hereinbefore (see e.g. process (a)), e.g. in the presence of a suitable solvent (e.g. water, a lower alkyl alcohol, acetonitrile, or mixtures thereof) and an appropriate base (e.g. sodium bicarbonate or potassium carbonate);
(iii) removal of the 
xe2x80x83fragment from the resultant compound of formula I to provide a compound of formula VII in which R1 represents straight- or branched-chain C1-4 alkyl (e.g. C1-3 alkyl, such as methyl) terminated by C(O)R5a or xe2x80x94N(H)C(O)OR10b, R5a and R10b independently represent straight- or branched-chain C2-6 alkyl (e.g. C3-5 alkyl, such butyl (e.g. t-butyl)), and R41 to R46 all represent H, for example under appropriate deprotection conditions, such as hydrogenation in the presence of a supported palladium catalyst (e.g. Pd/C), for example at room temperature in the presence of a suitable solvent (e.g. a lower alkyl alcohol, such as ethanol)); and
(iv) reaction of the resultant compound of formula VII with a compound of formula VIII as hereinbefore defined, in which R2 represents H or OH, R3 represents H, A represents C1 alkylene or linear C2 alkylene, B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(H)xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter two groups, Z is attached to the carbon atom bearing R2 and R3, and represents C1 alkylene or linear C2 alkylene), G represents CH and R4 is a single cyano group in the para-position relative to B, and L2 represents, for example, arenesulfonate (e.g. toluenesulfonate), for example under conditions described hereinbefore (see e.g. process (d)), such as at between room and reflux temperature, in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. a lower alkyl alcohol, such as ethanol).
The skilled person will appreciate that, if desired, the above steps may be performed in a different order to those that stated above, to provide the relevant compounds of formula I. For example, steps (iii) and (iv) may be carried out prior to steps (i) and (ii). Alternatively, steps (i) and (iii) (in either order) may be completed before steps (ii) and (iv) (in either order) are carried out. However, we prefer that the steps are performed in the above-stated order.
The process of making the compounds of formula I from compounds of formulae XLVIII and XXIV (i.e. via compounds of formula XLVII) may have the advantage that oxabispidine ring systems may be formed using fewer steps than methods described in the prior art, and, particularly, avoids the use of mercury-containing compounds (thereby eliminating the production of toxic, mercury-containing waste). This process offers a convenient synthetic route to key oxabispidine compounds, and allows differential protection at the nitrogen atoms.
Further, this process may have the advantage that compounds comprising the oxabispidine ring may be prepared in less time, more conveniently, and/or at a lower cost, than when prepared in processes described in the prior art.
Compounds of formulae III, V, VI, XI, XII, XIII, XVI, XVII, XVIII, XIX, XXI, XXII, XXIV, XXV, XXVII, XXVIII, XXIX, XXX, XXXA, XXXB, XXXC, XXXD, XXXE, XXXF, XXXG, XXXI, XXXII, XXXIIIA, XXXIIIB, XXXIVA, XXXIVB, XXXV, XXXVI, XLI, XLIII, XLIV and XLVI and derivatives thereof, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds defined herein may be converted to other claimed substituents using techniques well known to those skilled in the art. For example, hydroxy may be converted to alkoxy, phenyl may be halogenated to give halophenyl, nitro may be reduced to give amino, halo may be displaced by cyano, etc.
The skilled person will also appreciate that various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formulae I. For example, carbonyl may be reduced to hydroxy or alkylene, and hydroxy may be converted to halo.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the process described above, the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitable protecting groups for amino include benzyl, sulfonamido (e.g. benzenesulfonamido), tert-butyloxycarbonyl, 9-fluorenyl-methoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for amidino and guanidino include benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter. For example, we have found that removal of an xe2x80x94SO2R9 group from an oxabispidine ring may take place conveniently by employment of an appropriate strong acid, such as a hydrohalic acid (especially HBr) e.g. as described hereinbefore.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J. W. F. McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1999).
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Moreover, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All prodrugs of compounds of formula I are included within the scope of the invention.
Some of the intermediates referred to hereinbefore are novel. According to a further aspect of the invention there is thus provided: (a) a compound of formula II, as hereinbefore defined, or a protected derivative thereof, optionally in the form of a salt and/or a solvate; (b) a compound of formula IV, as hereinbefore defined, or a protected derivative thereof; (c) a compound of formula VII, as hereinbefore defined, or a protected derivative thereof (provided that R1 does not represent xe2x80x94S(O)2R9, wherein R9 represents unsubstituted phenyl). Preferred compounds of formula VII include those in which R1 does not represent C(O)OR7, in which R7 is tert-butyl; (d) a compound of formula X, as hereinbefore defined, or a protected derivative thereof; (e) a compound of formula XIV, as hereinbefore defined, or a protected derivative thereof; (f) a compound of formula XV, as hereinbefore defined, or a protected derivative thereof; (g) a compound of formula XX, as hereinbefore defined, or a protected derivative thereof; (h) a compound of formula XXIII, as hereinbefore defined, or a protected derivative thereof, provided that L2 does not represent iodo; (i) a compound of formula XXXIX, or a protected derivative thereof; and (j) a compound of formula XLII, or a protected derivative thereof.
Preferred compounds of formula II include those in which:
R41 to R46 all represent H;
G represents CH;
A represents a direct bond;
B represents a direct bond;
R2 represents H or C1-6 alkyl;
R3 represents H or C1-6 alkyl; and/or
R4 is absent or represents one to three halo, methyl, methoxy or nitro groups.
Particularly preferred compounds of formula II include those in which:
R2 and R3 both represent H, and R4 is absent, optionally in the form of a sulfate, hemisulfate or, especially, a hydrochloride (such as a dihydrochloride) salt, which salt is optionally a hydrate (e.g. a hemihydrate).
Preferred compounds of formula VII include those which are not:
tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.
Preferred compounds of formula XLVII include those in which the group R1 and the group 
are different, and as such include those compounds of formula XLVII in which:
R1 represents xe2x80x94C(O)XR7, xe2x80x94C(O)N(R8)R5d or xe2x80x94S(O)2R9 (wherein X, R5d, R7, R8 and R9 are as hereinbefore defined);
R2 and R3 do not together represent xe2x95x90O when A represents a direct bond.
Particularly preferred compounds of formula XLVII include those in which
R1 represents xe2x80x94S(O)2R9, wherein R9 represents aryl (such as phenyl, particularly unsubstituted phenyl);
G represents CH;
A represents a direct bond;
B represents a direct bond;
R2 represents H or C1-6 alkyl;
R3 represents H or C1-6 alkyl;
R4 is absent or represents one to three halo, methyl, methoxy or nitro groups, especially 2- or 4-fluoro, 2- or 4-chloro, 4-bromo, 4-methyl, 2,4,6-trimethyl, 4-methoxy, or 2- or 4-nitro.
Medical and Pharmaceutical Use
Compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
Thus, according to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals.
In particular, the compounds of the invention exhibit myocardial electrophysiological activity, for example as demonstrated in the test described below.
The compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias.
The compounds of the invention are thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.
In the treatment of arrhythmias, compounds of the invention have been found to selectively delay cardiac repolarization, thus prolonging the QT interval, and, in particular, to exhibit class III activity. Although compounds of the invention have been found to exhibit class III activity in s particular, in the treatment of arrhythmias, their mode(s) of activity is/are not necessarily restricted to this class.
According to a further aspect of the invention, there is provided a method of treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.
Pharmaceutical Preparations
The compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 25.0 mg/kg body weight at oral administration and about 0.005 to 10.0 mg/kg body weight at parenteral administration. Preferable ranges of daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration.
The compounds of the invention have the advantage that they are effective against cardiac arrhythmias.
Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I and/or class IV activity in addition to class III activity)) than, be more potent than, be longer acting than, produce fewer side effects (including a lower incidence of proarrhythmias such as torsades de pointes) than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
Biological Tests
Test A
Primary Electrophysiological Effects in Anaesthetised Guinea Pigs
Guinea pigs weighing between 660 and 1100 g were used. The animals were housed for at least one week before the experiment and had free access to food and tap water during that period.
Anaesthesia was induced by an intraperitoneal injection of pentobarbital (40 to 50 mg/kg) and catheters were introduced into one carotid artery (for blood pressure recording and blood sampling) and into one jugular vein (for drug infusions). Needle electrodes were placed on the limbs for recording of ECGs (lead II). A thermistor was placed in the rectum and the animal was placed on a heating pad, set to a rectal temperature of between 37.5 and 38.5xc2x0 C.
A tracheotomy was performed and the animal was artificially ventilated with room air by use of a small animal ventilator, set to keep blood gases within the normal range for the species. In order to reduce autonomic influences both vagi were cut in the neck, and 0.5 mg/kg of propranolol was given intravenously, 15 minutes before the start of the experiment.
The left ventricular epicardium was exposed by a left-sided thoracotomy, and a custom-designed suction electrode for recording of the monophasic action potential (MAP) was applied to the left ventricular free wall. The electrode was kept in position as long as an acceptable signal could be recorded, otherwise it was moved to a new position. A bipolar electrode for pacing was clipped to the left atrium. Pacing (2 ms duration, twice the diastolic threshold) was performed with a custom-made constant current stimulator. The heart was paced at a frequency just above the normal sinus rate during 1 minute every fifth minute throughout the study.
The blood pressure, the MAP signal and the lead II ECG were recorded on a Mingograph ink-jet recorder (Siemens-Elema, Sweden). All signals were collected (sampling frequency 1000 Hz) on a PC during the last 10 seconds of each pacing sequence and the last 10 seconds of the following minute of sinus rhythm. The signals were processed using a custom-made program developed for acquisition and analysis of physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).
The test procedure consisted of taking two basal control recordings, 5 minutes apart, during both pacing and sinus rhythm. After the second control recording, the first dose of the test substance was infused in a volume of 0.2 mL into the jugular vein catheter for 30 seconds. Three minutes later, pacing was started and a new recording was made. Five minutes after the previous dose, the next dose of test substance was administered. Six to ten consecutive doses were given during each experiment.
Data Analysis
Of the numerous variables measured in this analysis, three were selected as the most important for comparison and selection of active compounds. The three variables selected were the MAP duration at 75 percent repolarization during pacing, the atrio-ventricular (AV) conduction time (defined as the interval between the atrial pace pulse and the start of the ventricular MAP) during pacing, and the heart rate (defined as the RR interval during sinus rhythm). Systolic and diastolic blood pressure were measured in order to judge the haemodynamic status of the anaesthetised animal. Further, the ECG was checked for arrhythmias and/or morphological changes.
The mean of the two control recordings was set to zero and the effects recorded after consecutive doses of test substance were expressed as percentage changes from this value. By plotting these percentage values against the cumulative dose administered before each recording, it was possible to construct dose-response curves. In this way, each experiment generated three dose-response curves, one for MAP duration, one for AV-conduction time and one for the sinus frequency, (RR interval). A mean curve of all experiments performed with a test substance was calculated, and potency values were derived from the mean curve. All dose-response curves in these experiments were constructed by linear connection of the data points obtained. The cumulative dose prolonging the MAP duration by 10% from the baseline was used as an index to assess the class III electrophysiological potency of the agent under investigation (D10).
Test B
Glucocorticoid-treated Mouse Fibroblasts as a Model to Detect Blockers of the Delayed Rectifier K Current
IC50 for K channel blockade was determined using a microtitre plate based screen method, based on membrane potential changes of glucocorticoid-treated mouse fibroblasts. The membrane potential of glucocorticoid-treated mouse fibroblasts was measured using fluorescence of the bisoxonol dye DiBac4(3), which could be reliably detected using a fluorescence laser imaging plate reader (FLIPR). Expression of a delayed rectifier potassium channel was induced in mouse fibroblasts by 24 hours exposure to the glucocorticoide dexamehasone (5 xcexcM). Blockade of these potassium channels depolarised the fibroblasts, resulting in increased fluorescence of DiBac4(3).
Mouse ltk fibroblasts (L-cells) were purchased from American Type Culture Collection (ATCC, Manassa, Va.), and were cultured in Dulbeccos modified eagle medium supplemented with fetal calf serum (5% vol/vol), penicillin (500 units/mL), streptomycin (500 xcexcg/mL) and L-alaaine-L-glutamine (0.862 mg/mL). The cells were passaged every 3-4 days using trypsin (0.5 mg/mL in calcium-free phosphate buffered saline, Gibco BRL). Three days prior to experiments, cell-suspension was pipetted out into clear-bottom, black plastic, 96-well plates (Costar) at 25000 cells/well.
The fluorescence probe DiBac4(3) (DiBac Molecular probes) was used to measure membrane potential. DiBac4(3) maximally absorbs at 488 nM and emits at 513 nM. DiBac4(3) is a bisoxonol, and thus is negatively charged at pH 7. Due to its negative charge, the distribution of DiBac4(3) across the membrane is dependent upon the transmembrane potential: if the cell depolarizes (i.e. the cell interior becomes less negative relative to cell exterior), the DiBac4(3) concentration inside the cell increases, due to electrostatic forces. Once inside the cell, DiBac4(3) molecules can bind to lipids and proteins, which causes an increase in fluorescence emission. Thus, a depolarization will be reflected by an increase in DiBac4(3) fluorescence. The change in DiBac4(3) fluorescence was detected by a FLIPR.
Prior to each experiment, the cells were washed 4 times in phosphate-buffered saline (PBS) to remove all culture media. The cells were then treated with 5 xcexcM DiBac4(3) (in 180 xcexcL of PBS) at 35xc2x0 C. Once a stable fluorescence was reached (usually after 10 min), 20 xcexcL of the test substance was added, using FLIPR""s internal 96 well pipetting system. Fluorescence measurements were then taken every 20 sec for a further 10 min. All experiments were carried out at 35xc2x0 C., due to the high temperature sensitivity of both delayed rectifier potassium channel conductance and DiBac4(3) fluorescence. Test substances were prepared in a second 96 well plate, in PBS containing 5 xcexcM DiBac4(3). The concentration of substance prepared was 10 times that of the desired concentration in the experiment as an additional 1:10 dilution occurred during addition of substance during the experiment. Dofetilide (10 xcexcM) was used as a positive control, i.e. to determine the maximum increase in fluorescence.
Curve-fitting, used to determine the IC50 values, was performed with the Graphpad Prism program (Graphpad Software Inc., San Diego, Calif.).
Test C
Metabolic Stability of Test Compounds
An in vitro screen was set up to determine the metabolic stability of the compounds of the invention.
The hepatic S-9 fraction from dog, man, rabbit and rat with NADPH as co-factor was used. The assay conditions were as follows: S-9 (3 mg/mL), NADPH (0.83 mM), Tris-HCl buffer (50 mM) at pH 7.4 and 10 xcexcM of test compound.
The reaction was started by addition of test compound and terminated after 0, 1, 5, 15 and 30 minutes by raising the pH in the sample to above 10 (NaOH; 1 mM). After solvent extraction, the concentration of test compound was measured against an internal standard by LC (fluorescence/UV detection).
The percentage of test compound remaining after 30 minutes (and thus t1/2) was calculated and used as a measure for metabolic stability.